Insulin is perhaps the principal regulatory hormone governing fuel utilization in humans. Of the many molecules which stimulate insulin secretion, glucose is preeminent. Glucose is even necessary to allow many other islet stimulants to exert their effects, as the absence of the sugar renders these compounds powerless. In many diabetics the ability to perceive glucose as a provocative compound is impaired, resulting in hyperglycemia. The underlying causes of this derangement are unknown, a not too surprising situation considering the fact that the factors regulating release are still obscure. The present series of experiments attempts to define the factors which regulate the release of insulin. Because the metabolism of glucose has been implicated by numerous investigations as being an essential event governing secretion, particular attention will be focused on the biochemical pathways involved in the utilization of the sugar. The contribution of the various metabolic pathways which result not only in energy production but also, perhaps, in insulin secretion will be assessed using newly developed methodologies in which substrate metabolism is monitored simultaneous with insulin release. In an attempt to define the essential events governing hormone secretion, stimulatory as well as non-stimulatory sugars will be used. The effects of physiologic and pharmacologic probes on these metabolic parameters will be assessed. It is the contention of the applicant that a thorough understanding of the physiology of these intricate groups of cells will aid us, not only in designing more effective therapeutic agents, but also in the search for an explanation as to why these cells are so susceptible to pathogenic organisms resulting in their premature loss. Is there any relationship between islet cell receptor systems and their susceptibility to various pathogenic organisms? The experiments outlined represent a concerted effort to supply the necessary physiologic information to answer this important question.